Usefulness of minipigs for predicting human pharmacokinetics: Prediction of distribution volume and plasma clearance

Yoshimatsu, Hiromichi; Konno, Yasuhiko; Ishii, Kunikazu; Satsukawa, Masahiro; Yamashita, Shinji

doi:10.1016/j.dmpk.2015.11.001

Cited by 26 publications

(18 citation statements)

References 21 publications

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“…[7,8] Warfarin, alprazolam and diazepam also served as controls for the determination of f u,mic , the experimental values were 0.83, 0.85 and 0.91, respectively, and the f u,mic for flubromazolam was 0.82 (Table 4). The f u,p as well as f u,mic for the controls were in good agreement with reported values, [19,26,30,31] which indicated that the dialysis reached the equilibrium after the 24 h incubation period. Although the f u,mic of alprazolam and diazepam reported by Obach et al [19] are considerably lower than our experimental results, it is probably because of the higher microsomal protein concentration used by Obach et al (5 mg/mL) which suggests the f u,mic for these benzodiazepines is strongly influenced by the microsomal protein content, especially for diazepam.…”

Section: Plasma Protein and Non-specific Binding In Phlm And Predictisupporting

confidence: 91%

In vitro studies on flubromazolam metabolism and detection of its metabolites in authentic forensic samples

Noble

Mardal

Holm

et al. 2017

Drug Testing and Analysis

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Flubromazolam is a triazole benzodiazepine with high potency and long-lasting central nervous system depressant effects; however, limited data about its pharmacokinetics are available. Here, we report in vitro studies of the human flubromazolam metabolism analyzed by liquid chromatography high-resolution mass spectrometry (LC-HRMS). In vitro investigations were carried out in pooled human liver microsomes (pHLM) and recombinant cytochrome P450 (CYP)-enzymes. To confirm those metabolites detected in vitro, authentic samples obtained from two forensic cases were also analyzed by LC-HRMS. Additionally, determination of the unbound fraction of flubromazolam in pHLM and in plasma was performed by equilibrium dialysis with subsequent prediction of its hepatic clearance (CL ) using well-stirred and parallel-tube models. Additional findings obtained by routine screening methods of these forensic cases are also reported. Studies using incubations with nicotinamide adenine dinucleotide phosphate-fortified pHLM with or without uridine 5'-diphosphoglucuronic acid and incubations with CYP-enzymes identified the main metabolic pathway of flubromazolam as hydroxylation on the α- and/or 4-position mediated by CYP3A4 and CYP3A5, with subsequent glucuronidation of the hydroxylated metabolites as well as of the parent drug. Further, α-hydroxy-flubromazolam and its corresponding glucuronide were detected in vivo together with the N-glucuronide of flubromazolam. The predicted CL of flubromazolam using the well-stirred and parallel-tube models were 0.42 and 0.43 mL/min/kg, respectively. Based on the data presented here, flubromazolam is primarily metabolized by CYP3A4/5 with a high protein-binding and a predicted low clearance. Analysis of authentic samples suggested that analytical targets for flubromazolam should be the compound itself and α-hydroxy-flubromazolam. Copyright © 2016 John Wiley & Sons, Ltd.

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Section: Plasma Protein and Non-specific Binding In Phlm And Predictisupporting

confidence: 91%

In vitro studies on flubromazolam metabolism and detection of its metabolites in authentic forensic samples

Noble

Mardal

Holm

et al. 2017

Drug Testing and Analysis

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“…The method consisted of five steps: (1) developing the TCM, (2) estimating the tissue composition of several tissues of minipig to develop the TCM for that species, (3) predicting the V ss , (4) predicting the K p-dermis , and, finally, (5) presenting the data sets of drugs. The predicted values of V ss and K p-dermis were compared with experimentally determined values for several drugs showing different PK and physicochemical properties, which respect the criterion of a robust validation exercise.…”

Section: Methodsmentioning

confidence: 99%

“…The V ss in male minipigs aged 3 months of the strain Nippon Institute of Biological Science (NIBS) was predicted with the TCM for 19 marketed drugs for which complete data sets were available from the literature. 2,[34][35][36][37][38] Furthermore, 19 proprietary compounds from Nestl e Skin Health R&D were also investigated for which intravenous PK have been investigated in male G€ ottingen minipigs aged 9 months and for which all physicochemical and binding parameters have been determined experimentally during our routine screening in drug discovery. These 2 data sets used for V ss predictions are presented in Table 4.…”

Section: Prediction Of V Ssmentioning

confidence: 99%

“…1 Moreover, it is the animal model of choice for assessment of dermal absorption, local tolerance, and systemic toxicity following dermal exposures; hence, minipig is used routinely for pharmacological and toxicological issues because of its relatively similar responses to drugs compared to humans. 2,3 Furthermore, allometric scaling that included minipig data resulted in high accuracy in the prediction of human pharmacokinetics (PK) parameters such as the volume of distribution and clearance, clearly indicating the importance of minipig data. 4 Consequently, it is important to predict drug accumulation in plasma and dermis in minipig in early drug discovery because dermal PK in that species is used for selecting candidates for advancement into clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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Application of the Tissue Composition–Based Model to Minipig for Predicting the Volume of Distribution at Steady State and Dermis-to-Plasma Partition Coefficients of Drugs Used in the Physiologically Based Pharmacokinetics Model in Dermatology

Poulin

Collet

Atrux-Tallau

et al. 2019

Journal of Pharmaceutical Sciences

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“…Deguchi et al 65) evaluated the accuracy of predicting human CL t using the ROE and SSS with mouse, rat, monkey and dog PK data for UGT substrates. They reported that SSS using monkeys showed the most accurate prediction of human CL t .…”

Section: Prediction Of Human Pk Using Allome-tric Scalingmentioning

confidence: 99%

Utility of Chimeric Mice with Humanized Liver for Predicting Human Pharmacokinetics in Drug Discovery: Comparison with <i>in Vitro</i>–<i>in Vivo</i> Extrapolation and Allometric Scaling

Naritomi

Sanoh

Ohta

2019

Biological & Pharmaceutical Bulletin

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Predicting human pharmacokinetics (PK) such as clearance (CL) and volume of distribution (Vd) is a critical component of drug discovery. These predictions are mainly performed by in vitro-in vivo extrapolation (IVIVE) using human biological samples, such as hepatic microsomes and hepatocytes. However, some issues with this process have arisen, such as inconsistencies between in vitro and in vivo findings; the integration of predicted CYP, non-CYP and transporter-mediated human PK; and the difficulty of evaluating very metabolically stable compounds. Various approaches to solving these issues have been reported. Allometric scaling using experimental animals has also often been used. However, this method has also shown many problems due to interspecies differences, albeit that various correction methods have been proposed. Another approach involves the production of chimeric mice with humanized liver via the transplantation of human hepatocytes into mice. The livers of these mice are repopulated mostly with human hepatocytes and express human drug-metabolizing enzymes and drug transporters, suggesting that these mice are useful for solving the issues of IVIVE and allometric scaling, and more reliably predicting human PK. In this review, we summarize human PK prediction methods using IVIVE, allometric scaling and chimeric mice with humanized liver, and discuss the utility of predicting human PK in drug discovery by comparing these chimeric mice with IVIVE and allometric scaling.

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Usefulness of minipigs for predicting human pharmacokinetics: Prediction of distribution volume and plasma clearance

Cited by 26 publications

References 21 publications

In vitro studies on flubromazolam metabolism and detection of its metabolites in authentic forensic samples

In vitro studies on flubromazolam metabolism and detection of its metabolites in authentic forensic samples

Application of the Tissue Composition–Based Model to Minipig for Predicting the Volume of Distribution at Steady State and Dermis-to-Plasma Partition Coefficients of Drugs Used in the Physiologically Based Pharmacokinetics Model in Dermatology

Utility of Chimeric Mice with Humanized Liver for Predicting Human Pharmacokinetics in Drug Discovery: Comparison with <i>in Vitro</i>–<i>in Vivo</i> Extrapolation and Allometric Scaling

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